Abstract
Alzheimer’s disease is associated with a selective loss of cholinergic neurons located in the basal forebrain. Even though other neuronal systems are also partly affected, the loss of cholinergic neurons is regarded by most investigators as being the principal factor responsible for the memory loss that is characteristic of Alzheimer’s disease (Bartus et al., 1982; Coyle et al., 1983; Davies, 1985). In attempting to find the cause of and treatment for the disease, I decided to study the cell biology of cholinergic neurons of the forebrain and to characterise their requirements for survival and maintenance of function. A culture system was developed in which cholinergic neurons from rat brains are grown and studied under controlled conditions and are easily accessible for observation. Using these cultures, the effects of other cell types, growth factors, hormones and drugs on survival, growth and differentiation of cholinergic cells are investigated. These studies will lead to a characterisation of the conditions required by cholinergic neurons to survive and maintain their function in vitro. Conditions and compounds found to affect cholinergic neurons in vitro will later be assessed in living animals with specific lesions of the cholinergic systems. The in vitro studies first focussed on the effects of NGF and thyroxine, which were both reported to influence cholinergic neurons, and on gangliosides, which were claimed to promote neuronal survival and regeneration.
This is a preview of subscription content, log in via an institution.
Preview
Unable to display preview. Download preview PDF.
References
Agnati, L. F., Fuxe, K., Calza, L., Benefanti, F., Cavicchioli, L., Toffano, G., and Goldstein, M. (1983). Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function in striatum of rats by collateral sprouting. Acta Physiol Scand., 119, 347–63.
Ando, S. (1983). Gangliosides in the nervous system. Neurochem. Int., 5, 507–37.
Bartus, R. T., Dean, R. L., Beer, B., and Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217, 408–17.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 72, 248–54.
Byrne, M. C., Ledeen, F. J., Roisen, F. J., York, G., and Scalafani, J. R. (1983). Ganglioside-induced neuritogenesis: verification that gangliosides are the active agents, and comparison of molecular species. J. Neurochem., 41, 1214–22.
Ceccarelli, B., Aporti, F., and Finesso, M. (1976). Effects of brain gangliosides on functional recovery in experimental regeneration and reinnervation. Adv. Exp. Med. Biol., 71, 275–93.
Cheung, E. N. (1985). Thyroid hormone action: determination of hormone-receptor interaction using structural analogs and molecular modeling. Trends Pharmacol. Sci., Jan. 1985, 31–4.
Coyle, J. T., Price, D. L., and DeLong, M. R. (1983). Alzheimer’s disease: a disease of cortical cholinergic innervation. Science, 219, 1184–9.
Crutcher, K. A. (1982). Development of the rat septohippocampal projection: a retrograde fluorescent tracer study. Dev. Brain Res., 3, 145–50.
Crutcher, K. A., and Collins, F. (1982). In vitro evidence for two distinct hippocampal growth factors: basis of neuronal plasticity? Science, 217, 67–70.
Crutcher, K. A., and Davis, J. N. (1981). Sympathetic noradrenergic sprouting in response to central cholinergic denervations. Trends Neurosci., 4, 70–2.
Crutcher, K. A., Brothers, L., and Davis, J. N. (1979). Sprouting of sympathetic nerves in the absence of afferent input. Exp. Neurol, 66, 778–83.
Davies, P. (1985). Is it possible to design rational treatment for the symptoms of Alzheimer’s disease? Drug Develop Res., 5, 69–75.
Fonnum, F. (1975). A rapid radiochemical method for the determination of choline acetyltransferase. J. Neurochem., 24, 407–9.
Gnahn, H., Hefti, F., Heumann, R., Schwab, M., and Thoenen, H. (1983). NGF-mediated increase of choline acetyltransferase (ChAT) in the neonatal forebrain; evidence for a physiological role of NGF in the brain? Dev. Brain Res., 9, 45–52.
Gorio, A., Marini, P., and Zanoni, R. (1983). Muscle reinnervation. III. Motoneuron sprouting capacity, enhancement by exogenous gangliosides. Neuroscience, 8, 417–29.
Grave, G. D. (1977). Thyroid Hormones and Brain Development, Raven Press, New York.
Greene, L. A., and Shooter, E. M. (1980). The nerve growth factor: biochemistry, synthesis and mechanism of action. Ann. Rev. Neurosci., 3, 353–402.
Hefti, F. (1983). Alzheimer’s disease caused by a lack of nerve growth factor? Ann. Neurol., 13, 109–10.
Hefti, F. Dravid, A., and Hartikka, J. (1984). Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal lesions. Brain Res., 293, 305–9.
Hefti, F., Hartikka, J., and Frick, W. (1985b). Gangliosides alter morphology and growth of astrocytes and increase the activity of choline acetyltransferase in cultures of dissociated septal neurons. J. Neurosci., 5, 2086–94.
Hefti, F., Hartikka, J., Eckenstein, F., Gnahn, H., Heumann, R., and Schwab, M. (1985a). Nerve growth factor (NGF) increases choline acetyltransferase but not survival or fiber growth of cultured septal cholinergic neurons. Neuroscience, 14, 55–68.
Honegger, P. and Lenoir, D. (1980a). Nerve growth factor (NGF) stimulation of cholinergic telencephalic neurons in aggregating cell cultures. Dev. Brain. Res., 3, 229–38.
Honegger, P., and Lenoir, D. (1980b). Triiodothyronine enhancement of neuronal differentiation in aggregating fetal rat brain cells cultured in a chemically defined medium. Brain Res., 199, 425–34.
Jorgensen, E. C. (1978). In Li, C. H. (ed.), Hormonal Proteins and Peptides, Vol. 6. Academic Press, New York, pp. 108–204.
Kalaria, R. N., and Prince, A. K. (1985). The effects of neonatal thyroid deficiency on acetylcholine synthesis and glucose oxidation in rat corpus striatum. Dev. Brain Res., 20, 271–9.
Karpiak, S. E. (1983). Ganglioside treatment improves recovery of alteration behavior after unilateral entorhinal cortex lesion. Exp. Neurol, 81, 330–9.
Kiernan, J. A. (1979). Hypotheses concerned with axonal regeneration in the mammalian nervous system. Biol. Rev., 54, 155–97.
Kojima, M., Kim, J. S., Uchimurea, H., Hirano, M., Nakahaia, T., and Matsumoto, T. (1981). Effect of thyroidectomy on choline acetyltransferase in rat hypothalamic nuclei. Brain Res., 209, 227–30.
Loy, R., and Moore, R. Y. (1977). Anomalous innervation of the hippocampal formation by peripheral sympathetic axons following mechanical injury. Exp. Neurol., 57, 645–50.
Mesulam, M. M., Mufson, E. J., Wainer, B. H., and Levey, A. I. (1983). Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch. 1-Ch. 6). Neuroscience, 10, 1185–201.
Milner, T. A., Loy, R., and Amaral, D. G. (1983). An anatomical study of the development of the septo-hippocampal projection in the rat. Dev. Brain Res., 8, 343–71.
Morgan, J. I., and Seifert, W. (1979). Growth factors and gangliosides: a possible new perspective in neuronal growth control. J. Supramolec. Struc., 10, 111–24.
Nadler, J. V., Mattews, D. A., Cotman, C. W., and Lynch, G. S. (1974). Development of cholinergic innervation in the hippocampal formation of the rat. Dev. Biol., 36, 142–54.
Rybak, S., Ginzburg, I., and Yavin, E. (1983). Gangliosides stimulate neurite outgrowth and induce tubulin mRNA accumulation in neural cells. Biochem. Biophys. Res. Commun., 116, 974–80.
Schwab, M., Otten, U., Agid, Y., and Thoenen, H. (1979). Nerve growth factor (NGF) in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res., 168, 473–83.
Seiler, M., and Schwab, M. E. (1984). Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat. Brain Res., 300, 33–6.
Shelton, D. L., and Reichardt, L. F. (1984). Expression of the nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc. Natl Acad. Sci. USA, 81, 7951–5.
Stenevi, U., and Bjorklund, A. (1978). Growth of vascular sympathetic axons into the hippocampus after lesions of the septo-hippocampal pathway; a pitfall in brain lesion studies. Neurosci. Lett., 7, 219–24.
Suda, K., Barde, Y. A., and Thoenen, H. (1978). Nerve growth factor in mouse and rat serum: correlation between bioassay and radioimmunoassay determinations. Proc. Natl Acad. Sci. USA, 75, 4042–6.
Thoenen, H., and Barde, Y. A. (1980). Physiology of nerve growth factor. Physiol. Rev., 60, 1284–335.
Toffano, G., Savoini, G., Moroni, G., Lombardi, G., Calza, L., and Agnati, L. F. (1983). GM1 ganglioside treatment reduces dopamine cell body degeneration in the substantia nigra after unilateral hemitranssection in rat. Brain Res., 296, 233–9.
Toniolo, G., Dunnett, S. B., Hefti, F., and Will, B. (1985). Acetylcholine-rich transplants in the hippocampus: influence of intrinsic growth factors and application of NGF on choline acetyltransferase activity. Brain Res., 345, 141–6.
Valcana, T. (1971). Effect of neonatal hypothyroidism on the development of acetylcholinesterase and choline acetyl transferase activity in rat brain. In Ford, D. H. (ed.), Influence of Hormones on the Nervous System. S. Karger, Basel, pp. 174–84.
Wainer, B. H., Levey, A. I., Mufson, E. F., and Mesulam, M. M. (1984). Cholinergic systems in mammalian brain identified with antibodies against choline acetyltransferase. Neurosci. Int., 6, 163–82.
Editor information
Editors and Affiliations
Copyright information
© 1986 The Editors and the Contributors
About this chapter
Cite this chapter
Hefti, F. (1986). Cell Biology of the Forebrain Cholinergic Neurons: Effects of NGF, Triiodothyronine and Gangliosides. In: Briley, M., Kato, A., Weber, M. (eds) New Concepts in Alzheimer’s Disease. Palgrave, London. https://doi.org/10.1007/978-1-349-08639-9_13
Download citation
DOI: https://doi.org/10.1007/978-1-349-08639-9_13
Publisher Name: Palgrave, London
Print ISBN: 978-1-349-08641-2
Online ISBN: 978-1-349-08639-9
eBook Packages: MedicineMedicine (R0)